COVID-19: systemic pathology and its implications for therapy

Abstract

Responding to the coronavirus disease 2019 (COVID-19) pandemic has been an unexpected and unprecedented global challenge for humanity in this century. During this crisis, specialists from the laboratories and frontline clinical personnel have made great efforts to prevent and treat COVID-19 by revealing the molecular biological characteristics and epidemic characteristics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, SARS-CoV-2 has severe consequences for public health, including human respiratory system, immune system, blood circulation system, nervous system, motor system, urinary system, reproductive system and digestive system. In the review, we summarize the physiological and pathological damage of SARS-CoV-2 to these systems and its molecular mechanisms followed by clinical manifestation. Concurrently, the prevention and treatment strategies of COVID-19 will be discussed in preclinical and clinical studies. With constantly unfolding and expanding scientific understanding about COVID-19, the updated information can help applied researchers understand the disease to build potential antiviral drugs or vaccines, and formulate creative therapeutic ideas for combating COVID-19 at speed.

Full text

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International Journal of Biological Sciences
2022; 18(1): 386-408. doi: 10.7150/ijbs.65911
Review
COVID-19: systemic pathology and its implications for
therapy
Qi Shen1,2, Jie Li1,2, Zhan Zhang3,4, Shuang Guo5, Qiuhong Wang6, Xiaorui An1,2, Haocai Chang1,2
1. MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631,
China.
2. Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
3. Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
4. Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510120, China.
5. Dermatology Hospital, Southern Medical University, Guangzhou 510091, China.
6. Qilu Cell Therapy Technology Co., Ltd, Jinan 250000, China.
 Corresponding author: changhc@scnu.edu.cn, College of Biophotonics, South China Normal University, 55 West Zhongshan Avenue, Tianhe District,
Guangzhou 510631, China. Tel: +86-20-85210089; Fax: +86-20-85216052
© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
See http://ivyspring.com/terms for full terms and conditions.
Received: 2021.08.09; Accepted: 2021.11.04; Published: 2022.01.01
Abstract
Responding to the coronavirus disease 2019 (COVID-19) pandemic has been an unexpected and
unprecedented global challenge for humanity in this century. During this crisis, specialists from the
laboratories and frontline clinical personnel have made great efforts to prevent and treat COVID-19 by
revealing the molecular biological characteristics and epidemic characteristics of the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, SARS-CoV-2 has severe consequences
for public health, including human respiratory system, immune system, blood circulation system, nervous
system, motor system, urinary system, reproductive system and digestive system. In the review, we
summarize the physiological and pathological damage of SARS-CoV-2 to these systems and its molecular
mechanisms followed by clinical manifestation. Concurrently, the prevention and treatment strategies of
COVID-19 will be discussed in preclinical and clinical studies. With constantly unfolding and expanding
scientific understanding about COVID-19, the updated information can help applied researchers
understand the disease to build potential antiviral drugs or vaccines, and formulate creative therapeutic
ideas for combating COVID-19 at speed.
Key words: SARS-CoV-2, immune system, nervous system, reproductive system, motor system, immunotherapy
1. Introduction
Coronavirus disease 2019 (COVID-19) with acute
respiratory disease and potentially severe pneumonia
has resulted in unimaginable consequence to public
health and loss of human life due to severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2).
As the end of 5 November 2021, there have been
248,467,363 confirmed cases of COVID-19, including
5,027,183 deaths (https://covid19.who.int/). The
focus of global efforts is to develop safe and effective
vaccines against COVID-19, and some vaccines are
provisionally licensed for COVID-19 prevention.
However, the population of COVID-19 patients is still
surging in the case of public vaccination.
As reported, SARS-CoV-2 is a single-stranded
positive-sense RNA virus, whose genome size varies
from 29.8 ~ 29.9 kb [1], and whose genome encodes 4
structural proteins (spike surface glycoprotein (S),
membrane protein, envelope protein and
nucleocapsid protein), 16 non-structural proteins
(NSP1-16) and some accessory proteins (ORF3a,
ORF3b, ORF6, ORF7a, ORF7b, ORF8, ORF9b and
ORF10) [2-4] (Fig. 1). With unremitting efforts of
scientific researchers around the world, the structure
and function of these proteins have been more
understood. However, effective treatment including
drug or vaccine is still not available for COVID-19, the
study on SARS-CoV-2 still needs to be explored. So
far, few studies have systematically investigated the
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physiological and pathological features of
SARS-CoV-2 from a multisystem perspective (Fig. 1).
In this review, the information about the
characteristics, damage and treatment of SARS-CoV-2
is summarized and updated by our limited
understanding. Importantly, we have tried to give a
full insight into physiological effects and action
mechanisms of SARS-CoV-2 in order to find potential
therapeutic strategies or control measures in this way
to combat the ongoing infection.
2. Affect and Effect of COVID-19
2.1. COVID-19 on respiratory system
Obviously, respiratory system is the first to bear
the brunt of SARS-CoV-2, which as a danger signaling
is sent to immune system. As a receptor of S surface
protein on SARS-CoV-2, angiotensin converting
enzyme II (ACE2) is mainly expressed in type-2
alveolar (AT2) cells (83% in average) [5] and other
certain cells such as epithelial cells, which exists
widely in various tissues and organs including oral
mucosa [6], airway [7], lung [8], colon [9], kidney [10]
and prostate [11]. Depending on the context, lungs are
directly under the strongest attack to cause lung
inflammation and functional injury. As a result,
pulmonary fibrosis occurs frequently in the infected
patients, along with dry cough, dyspnea and fatigue
symptoms.
Pulmonary fibrosis is characterized by the
excessive deposition of extracellular matrix
components including collagen and fibronectin,
mainly originating from the persistence of fibroblast
proliferation and activation. A molecular explanation
for pulmonary fibrosis is that fibroblast growth factor
(FGF) and transforming growth factor (TGF), as
inducers of collagen and fibronectin [12, 13], are both
high levels in COVID-19 patients [14, 15]. As reported,
other upregulated pro-inflammatory cytokines, such
as platelet-derived growth factor (PDGF), vascular
endothelial growth factor (VEGF), tumor necrosis
factor α (TNFα) and interleukin-6 (IL-6), also involved
in the process [16]. Another important aspect is that
ongoing AT2 epithelial cell injury can recruit
fibroblasts to fibrotic loci, and then fibroblasts
differentiate into myofibroblasts to produce
extracellular matrix proteins [16, 17].
2.2. COVID-19 on immune system
An effective immune response against
SARS-CoV-2 requires two arms of the immune
system, the innate immune system and the adaptive
immune system. The innate immune system, as the
first line of defense of the immune system, is
responsible for rapidly recognizing the infection and
triggering alarms, in which a range of innate immune
cells are involved. On the other hand, the adaptive
immune system is essential for controlling and
clearing the viral infection, the three fundamental
components of which (CD4+ T cells, CD8+ T cells, B
cells) cooperate with each other to regulate the
antigen-specific immune responses. Therefore,
understanding the interaction between SARS-CoV-2
and the immune system is of great importance for
pathogenesis, disease progression, treatment
strategies, and vaccine design of COVID-19.
Figure 1. Structure of SARS-CoV-2 and its infection on tissues and organs in eight major systems of human organism.

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Figure 2. The immunopathology of SARS-CoV-2. SARS-CoV-2 reduced the number of monocytes, NK cells, DCs, CD4+ T cells, CD8+ T cells and B cells. Conversely, the virus
increased the number of neutrophils, mast cells, macrophages, memory CD4+ T cells, memory CD8+ T cells and memory B cells to some extent, and triggered complement
system responses, then the host produced a strong and harmful cytokine storm, and a weak and favorable antibody response.
2.2.1. Innate immune response
The innate immune response correlates with the
severity of COVID-19, which has been proved by a
range of studies [18, 19]. The innate immune system
against SARS-CoV-2 infection has three main
pathways: (1) limiting virus replication in infected
cells; (2) development of antiviral state in the infection
site, including recruitment of various innate immune
cells; (3) initiating the adaptive immunity [20]. All of
these pathways require the involvement of multiple
types of innate immune cells, of which the more
common cells are granulocytes, monocytes,
macrophages and natural killer (NK) cells, but there
are also many other immune cells including different
dendritic cells (DCs), innate lymphoid cells, and mast
cells.
2.2.1.1. Granulocytes and monocytes
A few studies have revealed that increases in
monocytes, neutrophils and eosinophils correlate
with the severity of disease in COVID-19 patients [21]
(Fig. 2). Liu found that the neutrophil-to-lymphocyte
ratio (NLR) could be served as a risk factor for
early-stage prediction of COVID-19 patients, whose
age is over 50 years old and NLR is more than 3.13 are
more likely predicted to develop critical illness [22]. A
prominent higher proportion of neutrophils and
activated mast cells was also observed in the
bronchoalveolar lavage fluid (BALF) of COVID-19
patients [18] (Fig. 2). The fact that chemoattractants
for neutrophils were upregulated during COVID-19
[19, 23, 24] suggested that granulocytes may
significantly contribute to pathogenesis.
CD16+ monocytes were depleted in COVID-19
patients and were remodeled with a phenotypic shift
toward CD14+ monocytes [24]. Inflammatory
HLA-DRhi CD11chi CD14+ monocytes can be
considered as a hallmark of mild COVID-19 patients
[25]. Moreover, decrease of CD14lo CD16hi monocytes
and the appearance of dysfunctional monocytes with
low expression of human leukocyte antigen class DR
(HLA-DR) and high expression of alarming S100 were
related to the severe COVID-19 patients [24, 25].
Interestingly, Guo et al. found a unique subpopulation
of monocytes, with high expression of inflammatory
genes, specifically present in the severe COVID-19
cases. These inflammatory genes were potentially
regulated by the transcription factors ATF3, NFIL3,
and HIVEP2 [26]. And COVID-19 patients were
reported to have greater abundance of CD14+ IL-1β+
and IFN-activated monocytes compared to healthy
controls [27]. These data suggest the potential risk of
inflammatory cytokine storms caused by monocytes.
In addition, ISGs upregulation in monocytes was
heterogeneous, with no clear relevance of COVID-19
severity [24].
2.2.1.2. Macrophages and DCs
Proinflammatory monocyte-derived macro-
phages had higher abundance in the BALF from
severe COVID-19 than mild cases [28]. Further
analysis of the heterogeneity of macrophages in
severe and mild patients found that the mild patients

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highly expressed FABP4, while the severe patients
highly expressed FCN1 and SPP1. These data suggest
the imbalance of lung macrophage populations in
COVID-19 patients. In general, a highly
proinflammatory macrophage microenvironment is
present in the lungs of severe COVID-19 patients,
which may contribute to recruitment of other innate
immune cells and tissue damage. Additional data
showed that macrophages in the lower airways had a
stronger inflammatory signature than those within
the upper airways [29]. Conventional DCs (cDCs) and
plasmacytoid DCs (pDCs) have been reported to
significantly decrease in BALFs of patients with
severe COVID-19 [28]. Sánchez-Cerrillo et al. found
that CD1c+ cDCs preferentially migrated from blood
to lungs in severe COVID-19 cases, whereas CD141+
cDCs and CD123hi pDCs were depleted from blood
and were also absent in the lungs [30]. Another study
found a decrease in the resting DCs and an increase in
the activated DCs in the lungs of COVID-19 cases [24].
2.2.1.3. NK cells
Accumulating studies have reported low levels
of NK cells in the peripheral blood of COVID-19
patients with moderate and severe disease [24, 31, 32].
However, two reports assessing the immune cells in
BALF of COVID-19 patients have revealed that NK
cells are increased at this infection site [28, 29].
Maucourant et al. found low numbers but a strong
activation phenotype (Ki-67+, HLA-DR+, CD69+) of
NK cells in peripheral blood of COVID-19 patients
and adaptive NK cells, with high expression of
perforin, NKG2C, and Ksp37, was increased in
circulation of patients with severe COVID-19 [33].
Analysis of NK cell transcriptomic signatures
furthermore confirmed that the increased expression
of cytotoxic marker PRF1 and repair marker DDIT4 in
NK cells was associated with recovered COVID-19
patients [34]. In contrast, another study found
NKG2A, an inhibitory receptor, has been upregulated
on peripheral NK cells, meanwhile, the expressions of
the activation markers CD107a, IFN-γ, IL-2, and TNFα
were decreased. These results suggest the functional
exhaustion of peripheral NK cells in COVID-19
patients [31]. Moreover, in convalescent patients, the
frequency of NK cells was restored [31, 35].
2.2.1.4. Complement system
The complement system is a key component of
innate immune response to clear pathogens and
serves as a danger-sensing alarming system. Patients
with COVID-19 have been reported with the
activation of the complement system, and intense
complement activation was related to severe disease
[36]. COVID-19 patients showed the complement
activation in their lung, sera, and other organ tissue
[37, 38]. Mannose-associated serine protease 2
(MASP-2) is the critical component for mediating
activation of the lectin pathway. Nucleocapsid protein
of SARS-CoV-2 was found to interact with MASP-2
[38], which led to a strong complement activation and
further aggravated lung injury. Complement
activation products in COVID-19 patients included
the classical/lectin (C4d), alternative (C3bBbP) and
common pathway (C3bc, C5a, and sC5b-9), the lectin
pathway recognition molecule mannose-binding
lectin (MBL). Among which, sC5b-9 and C4d were
significantly higher in patients with respiratory
failure than without respiratory failure [37] (Fig. 2).
Similarly, complement 6 and complement factor B, as
the components of complement system, have been
reported to be elevated in serum of patients with
COVID-19, suggesting that the complement activation
is an early immune response mechanism [39].
2.2.1.5. Cytokine storm
It was observed that the cytokine storm was
associated with disease severity of COVID-19. A
clinical investigation of 41 confirmed cases infected
with SARS-CoV-2 in China revealed that the initial
plasma concentrations of IL-1B, IL-1RA, IL-7, IL-8,
IL-9, IL-10, basic FGF, G-CSF, GM-CSF, IFN-γ, IP10,
MCP1, MIP1A, MIP1B, PDGF, TNFα, and VEGF were
higher compared to healthy individuals [21]. Further
analysis of both ICU and non-ICU patients found that
ICU patients exhibited higher plasma concentrations
of IL-2, IL-7, IL-10, G-CSF, IP10, MCP1, MIP1A, and
TNFα than non-ICU patients [21]. Similarly,
additional studies quantified cytokines and
chemokines in serum samples of COVID-19 patients,
and the results showed remarkable increases in
circulating levels of IL-6, IL-1RA, CCL2, CCL8
CXCL2, CXCL8, CXCL9, and CXCL16 [19]. The
significant increased chemokines are likely
responsible for the recruitment of neutrophil (CXCL1,
CXCL2, CXCL6) and monocyte (CCL2 and CCL8) to
the lungs [19]. However, it is worth mentioning that
whole blood RNA levels of cytokines were not always
consistent with protein plasma levels. For example,
IL-6 had not detected an increase at the transcriptional
level in the peripheral blood of COVID-19 patients,
but there is a large amount of IL-6 protein. TNFα was
only moderately upregulated at the transcriptional
level, while circulating TNFα was significantly
increased [40, 41].
The interferon system plays an important role in
antiviral immunity, and it is critical to understand the
IFN response in COVID-19. An immune analysis
based on a cohort of 50 COVID-19 patients revealed
that type I IFN response was high in mild to moderate
patients, whereas severe patients had significantly

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lower type I IFN responses than mild-to-moderate
patients [41]. In contrast to severe influenza,
COVID-19 patients exhibited a hyperinflammatory
profile in their peripheral blood mononuclear cells,
with a particular upregulation of TNF/IL-1β-driven
inflammatory responses, and type I IFN responses
coexist with TNF/IL-1β-driven inflammation in
monocytes from severe COVID-19 patients [42]. These
observations were consistent with an enhanced
expression of ISGs in patients with COVID-19 [41, 43].
Zhou et al. reported that the expression of 83 ISGs was
significantly upregulated in COVID-19 patients,
including IFITMs with direct antiviral activity,
compared with community-acquired pneumonia
patients [18]. However, in in vitro infection model
using cell lines, SARS-CoV-2 only induced low levels
of type I and type II IFNs, as well as moderate levels
of ISGs and a distinct proinflammatory cytokine
profiles including IL-1B, IL-6 and TNF, and many
chemokines (CCL20, CXCL1, CXCL2, CXCL3, CXCL5,
CXCL6 and CXCL16) [19, 40], resulting in efficiently
restricting SARS-CoV-2 infection. A longitudinal
immunological analysis of COVID-19 revealed that
IFNα and IFNλ in moderate patients were high levels
during the early phase and then declined, whereas
IFNα and IFNλ in severe patients showed a
continuous increase in overall [23]. The dynamic
changes of type I IFNs in COVID-19 patients suggest
that type I IFNs do not control the replication of
SARS-CoV-2 in vivo but are important drivers of the
disease progression.
2.2.2. Adaptive immune response
The adaptive immune response is critical for
controlling and eliminating most viral infections.
Studies of COVID-19 patients have observed that
adaptive immune response limits COVID-19 disease
severity and balanced CD4+ T cell, CD8+ T cell, and
antibody responses are protective, significantly
associated with milder disease. Understanding the
quantity and function changes in the three branches
(B cells, CD4+ T cells and CD8+ T cells) of adaptive
immune system in COVID-19 patients will provide
insights into immunity and pathogenesis of
SARS-CoV-2 infection, and the same knowledge also
contributes to the vaccine development and
evaluation of candidate vaccines.
2.2.2.1. Lymphopenia
Lymphopenia is prevalent in patients with
COVID-19 and is correlated with increased disease
severity. Patients who suffered COVID-19 showed
lower total blood lymphocyte compared to healthy
individuals, including a significant decrease in counts
of CD4+ T cells, CD8+ T cells, NK cells and NKT cells
[23]. The lymphocyte percentages were mostly lower
than 20% in severe patients, who were more likely to
exhibit lymphopenia than mild/moderate patients
[44]. Moreover, further analysis revealed that patients
with severe COVID-19 had a remarkable decrease in T
cells counts, but not B cells, especially CD8+ T cells
compared with moderate patients. These clinical data
suggest that lymphopenia can be used as one of the
effective indicators of disease severity and prognostic
evaluation in COVID-19 patients.
2.2.2.2. CD4+ T cells
Studies have noted that circulating
SARS-CoV-2-specific CD8+ and CD4+ T cells existed in
70% and 100% of convalescent COVID-19 patients
respectively [45], indicating that almost all
SARS-CoV-2 infections elicit the T cell response,
especially CD4+ T cell responses. Structural proteins
(spike, membrane, and nucleocapsid) of SARS-CoV-2
are the prominent targets of SARS-CoV-2-specific
CD4+ T cells. Additional CD4+ T cell responses also
against NSP3, NSP4, open reading frame (ORF) 3a,
and ORF8 [45]. SARS-CoV-2-specific CD4+ T cells can
be detected as early as 2-4 days after the onset of
symptoms [46, 47], which occurred in mild COVID-19
patients, accelerating viral clearance. Conversely, the
delayed appearance of SARS-CoV-2-specific CD4+ T
cells was associated with severe or fatal COVID-19 (>
22 days after the onset of symptoms in some cases)
[46, 47]. Moreover, SARS-CoV-2-specific CD4+ T cells
in severe COVID-19 patients displayed low antigen
avidity and clonality [48].
Virus-specific CD4+ T cells have the capacity for
differentiation into multiple helper and effector cell
types in response to SARS-CoV-2, which recruit
innate cells and provide help to B cells and CD8+ T
cells, with the abilities of direct antiviral activities and
facilitating tissue repair. Studies have been revealed
that the SARS-CoV-2-specific CD4+ T cells from both
acute and convalescent COVID-19 patients mainly
produced IFN-γ, TNF and IL-2, the classical cytokines
signature during type I T helper (Th1) cell responses,
with direct antiviral functions [45, 46, 49]. Another
branch of CD4+ T cells in immune responses against
SARS-CoV-2 is the differentiated T follicular helper
cells (Tfh), whose primary function is to assist B cells
in proliferation and neutralizing antibody production,
participating in humoral immunity. It has been found
that SARS-CoV-2-specific circulating Tfh cells (cTfh)
were a substantial fraction of the SARS-CoV-2-specific
CD4+ T cells in acute and convalescent COVID-19
patients [46]. And, the higher cell frequencies of
SARS-CoV-2-specific cTfh have been associated with
lower disease severity [46]. Cytotoxic T helper cells
(CD4-CTLs) are related cells with direct cytotoxic

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activity. Besides cytotoxicity-associated transcripts,
the SARS-CoV-2-specific CD4-CTL were highly
enriched for transcripts encoding for a range of
chemokines such as CCL3, CCL4 and XCL1. These
chemokines participate in the recruitment of myeloid
cells (neutrophils, monocytes, and macrophages), NK
cells, and DCs to the sites of viral infection [50].
According to the relevant data, the proportion of
CD4-CTLs and antigen-specific regulatory T cells
(Tregs) exhibited an obvious negative correlation [51].
2.2.2.3. CD8+ T cells
CD8+ T cells are important in clearing viral
infections due to their capacity for killing infected
cells. In COVID-19 patients, the presence of
SARS-CoV-2-specific CD8+ T cells has been related to
less severe disease [46]. Similarly to SARS-CoV-
2-specific CD4+ T cells, SARS-CoV-2 CD8+ T cells are
specific for multiple SARS-CoV-2 antigens, such as
spike, nucleocapsid, membrane and ORF3a protein
[45]. SARS-CoV-2-specific CD8+ T cells can be
detected as early as day 1 post-symptom onset [52].
The data showed that SARS-CoV-2-specific CD8+ T
cells were detected in 87% of convalescent COVID-19
cases but only in 53% of acute cases [46]. In the acute
COVID-19 cases, SARS-CoV-2-specific CD8+ T cells
were characterized by activation marker (CD38,
HLA-DR, and Ki-67) and predominantly expressed
IFN-γ, granzyme B, perforin, and CD107a, with
cytotoxic effector functions [45, 53]. However,
SARS-CoV-2-specific CD8+ T cells in convalescent
COVID-19 patients tended to an early differentiated
memory phenotype (CCR7+ CD127+ CD45RA-/+
TCF1+) [54]. From the foregoing, increasing the
number of CD4 and CD8 T cells through the
combination of other therapeutic approaches may be a
better method for the treatment of COVID-19 patients,
including the use of drug (such as CD3 antibody and
CD28 antibody [55]) and drug-free (such as
phototherapy [56]) therapeutic strategies.
2.2.2.4. Antibody response
The SARS-CoV-2 infected individuals exhibited
seroconversion within 20 days after symptom onset
[24, 57, 58]. Seroconversion for immunoglobulin (Ig)
M and IgG antibodies against SARS-CoV-2 occurred
simultaneously or sequentially [57]. A study based on
173 COVID-19 patients revealed that the
seroconversion rates for total antibodies, IgM, and
IgG were 93.1%, 82.7%, and 64.7%, respectively [59].
The spike and nucleocapsid of SARS-CoV-2 are
primary antigens testing for seroconversion [60].
Spike is the main target of neutralizing antibodies
against SARS-CoV-2, and its receptor binding domain
(RBD) is the target of more than 90% of neutralizing
antibodies in COVID-19 patients [60, 61], whereas
some other neutralizing antibodies instead target the
NTD [61]. Moreover, most COVID-19 patients had
detectable IgG and IgA responses to spike and
nucleocapsid, whereas IgM responses were limited to
spike and undetectable for nucleocapsid [60].
Among most SARS-CoV-2-infected patients,
neutralizing antibodies developed rapidly. Zhao’s
data showed that the antibodies were less than 40%
within 1 week since onset, and could rapidly increase
to 100.0% (total antibodies), 94.3% (IgM), and 79.8%
(IgG) within 15 days [59]. And neutralizing antibodies
titers stayed relatively stable for at least 5 months [62].
Additionally, it is worth noting that SARS-CoV-2
neutralizing antibody titers are positively correlated
with COVID-19 disease severity [57, 60, 63].
Consistently, most convalescent cases who recover
from COVID-19 do not exhibit high levels of
neutralizing antibodies activity. These antibodies had
little somatic hypermutation and were highly
enriched for the usage of gene VH1-69, VH3-30-3, and
VH1-24 [61]. Furthermore, the production of
SARS-CoV-2 neutralizing antibodies did not require
affinity maturation. Collectively, these data suggest
that the neutralizing antibodies against SARS-CoV-2
are relatively easy to generate.
2.2.2.5. Immune memory
Immunological memory is composed of memory
CD4+ T cells, memory CD8+ T cells and memory B
cells. All three major types of immune memory are
substantially generated after SARS-CoV-2 infection.
About 95% of individuals kept immune memory at ~6
months after SARS-CoV-2 infection [64].
About 90% of subjects are seropositive for
SARS-CoV-2 neutralizing antibodies at 6 to 8 months
after symptom onset [64]. SARS-CoV-2 RBD IgM and
IgG titers steadily decreased within 1 to 6 months
after infection, whereas IgA was less declined
relatively [65]. One cross-sectional analysis of
COVID-19 subjects has revealed that SARS-CoV-2
specific memory B cells were detectable in all subjects
at 6 months post-infection. Moreover, the frequencies
of memory B cells specific to spike, RBD, and
nucleocapsid increased over time in the following 4 to
5 months post-infection and then plateaued [64]. RBD
memory B cells had undergone affinity maturation
after infection 6 months and expressed the increased
potency neutralizing antibodies, indicating
continuous evolution of humoral immunity [65].
The memory CD4+ T cells predominantly
consists of Th1 and Tfh cells [64, 66]. The majority of
SARS-CoV-2 memory CD8+ T cells were mainly
terminally differentiated effector memory cells
(TEMRA), with small populations of central memory
(TCM) and effector memory (TEM) [64]. A few studies

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have assessed memory CD4+ T cells and CD8+ T cells
at least 6 months after infection. One study found that
~90% of subjects were positive for SARS-CoV-2
memory CD4+ T cells and ~50% were positive for
memory CD8+ T cells after 6 months primary infection
[64]. There was a steady decline in SARS-CoV-2
memory CD8+ T cells and CD4+ T cells within 8
months after infection.
2.3. COVID-19 on blood circulation system
2.3.1. Hematologic Parameters of COVID -19
Patients with COVID-19 usually present with
abnormal hematologic changes, including white
blood cells reduction, lymphopenia, and
thrombocytopenia. Based on the clinical data of 1099
COVID-19 cases provided by Guan et al. [67], the vast
majority of patients on admission presented with
lymphocytopenia (83.2%), whereas 36.2% had
thrombocytopenia, and 33.7% showed leukopenia.
And these hematological abnormalities were more
prominent in severe versus non-severe cases.
Several factors may contribute to COVID-19
associated lymphopenia. On the one hand, previous
study showed that lymphocytes expressed the ACE2
receptor on their surface [6], thus SARS-CoV-2
directly infected those cells and eventually led to cell
lysis. On the other hand, the virus particles
disseminate through the respiratory mucosa and
infect other cells, inducing a cytokine storm in the
body. It is characterized by markedly increased levels
of interleukins (IL-2, IL-6, IL-8), G-CSF, IFN-γ
inducible protein (IP-10) and TNFα, which promote
lymphocyte apoptosis [68-70]. Furthermore, massive
cytokine activation may be also associated with
atrophy of lymphoid organs, including the spleen,
and further impairs lymphocyte turnover [71].
2.3.2. COVID-19 and cardiovascular system
Patients with prior cardiovascular disease are at
higher risk for adverse events from COVID-19.
Individuals without a history of cardiovascular
disease are at risk for incident cardiovascular
complications [72]. The vast majority of COVID-19
patients with previous cardiovascular disease
presented with cardiovascular complications
including hypertension (40%) [73, 74], whereas 10%
had coronary heart disease, 17% had cardiac
arrhythmias, and 4% showed heart failure [22, 75].
Patients with more severe clinical presentations
present with comorbidities such as hypertension
(58%), heart disease (25%), and arrhythmias (44%) [76,
77]. Additionally, cardiovascular manifestations,
during COVID-19, are mostly represented by acute
cardiac injury (ACI), defined as a rise of cardiac
troponin values, with or without ejection fraction
decline or electrocardiographic abnormalities. The
prevalence of acute cardiac injury among COVID-19
patients was 10-23% [21].
Furthermore, COVID-19 patients are also at an
increased risk of venous thromboembolism and their
main coagulation parameters (elevated D-Dimer
levels, fibrin degradation products) are also altered,
especially in patients with severe manifestations [72].
The direct effects of COVID-19 or the indirect effects
of infection, such as severe illness and hypoxia, may
predispose patients to thrombotic events. Preliminary
reports suggest that hemostatic abnormalities,
including disseminated intravascular coagulation
(DIC), occur in patients affected by SARS-CoV-2 [78,
79]. Additionally, the severe inflammatory response,
critical illness, and underlying traditional risk factors
may all predispose to thrombotic events [79, 80].
Overall, patients with cardiovascular disease
represent more than 20% of all fatal cases, with a case
fatality rate of 10.5% [75].
2.4. COVID-19 on nervous system
Similar to other coronaviruses (mainly
SARS-CoV-1, MERS-CoV and OC43), the possibility
of SARS-CoV-2 invading the central nervous system
has been proposed [81]. In vivo studies in human
ACE2 transgenic mice have shown that SARS-CoV-2
can infect neurons and cause neuronal death in an
ACE2 dependent manner [82]. In brain cells derived
from human pluripotent stem cells, dopaminergic
neurons (rather than cortical neurons or microglia) are
particularly sensitive to SARS-CoV-2 infection [83].
However, the results of clinicopathological studies on
the detection of virus in brain or cerebrospinal fluid
(CSF) are different. Some studies have shown that
SARS-CoV-2 RNA exists in the brain or cerebrospinal
fluid of patients with encephalopathy or encephalitis
after death, but the level is very low [84]. Other
studies have failed to detect viral invasion, even if
there is evidence of CSF inflammation [85, 86]. Recent
studies have shown that SARS-CoV-2 can enter the
brain through damaged blood-brain barrier (BBB),
olfactory bulb/olfactory nerve or lymphatic vessels
[87]. SARS-CoV-2 can infect and directly cause
endothelial cell damage, increase BBB permeability,
and cause edema formation. It has been reported that
ACE2 is expressed in physiological conditions in
neurons and glial cells, making the brain more
vulnerable to SARS-CoV-2 infection [88]. Infected
neurons release inflammatory molecules and activate
nearby immune cells, including mast cells, endothelial
cells, pericytes, neurons, microglia and astrocytes.
When ACE2 is expressed in brain endothelial cells,
SARS-CoV-2 infection can cause cerebral hemorrhage
and BBB dysfunction [89], leading to endothelial cell

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damage, brain edema formation, neuronal death and
cognitive decline (Fig. 3). In addition, researches
demonstrated that ACE2 is also expressed in
pericytes, another apart of mural cells of the central
nervous system (CNS). SARS-CoV-2 may directly
destroy pericyte and further reduce blood supply to
the brain, and ultimately result in neuronal
dysfunction [90, 91]. Pericytes are perivascular cells
within the brain that are proposed as SARS-CoV-2
infection points [92]. Moreover, the infection of
olfactory bulb pericytes may disrupt neuronal signals
through local inflammation and cytokine release,
which are related to the functional impairment caused
by olfactory bulb vascular injury and hypoperfusion
[92]. A recent study shows that SARS-CoV-2 could
preferentially infect astrocyte over other cells [93].
They exposed the brain organoids to SARS-CoV-2 and
found that almost only astrocytes were infected.
Similarly, Daniel Martins-de-Souza et al. analyzed the
brains of 26 COVID-19 deceased, among 5 samples in
which the brain cells were infected with the
SARS-CoV-2, up to 66% of the infected cells were
indeed astrocytes [94].
Severe neurological complications in COVID-19
are both rare and variable in nature. Indeed, any part
of neuraxis seems to be susceptible to damage by
SARS-CoV-2. Neurological disorders may result from
systemic cardiopulmonary failure and metabolic
abnormalities caused by infections, direct viral
invasion, or viral autoimmune reactions. In an
unpublished report from Wuhan, China, 78 (36.4%) of
214 hospitalized COVID-19 patients had some form of
neurological disorder, the most common features of
which were dizziness, headache, hypogeusia, and
hyposmia [95]. While serious neurological
complications have been reported in patients with
otherwise mild COVID-19 [96], the most severe
complications occur in critically ill patients and are
Figure 3. Brain entry of SARS-CoV-2. Circulating SARS-CoV-2 and cytokines act on endothelial cells, leading to inflammation and BBB opening. Once in the perivascular space,
these factors induce inflammation in vascular parietal cells, microglia and macrophages resident in the brain. The cytokines may affect the function of neurons and lead to cytokine
sickness, which is a potential cause of COVID-19 encephalopathy.

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associated with significantly higher mortality [83, 97].
And neurological disorders were found to be more
common in critically ill patients, such as stroke in 6
(2.8%), impaired consciousness in 16 (7.5%), and
muscle injury in 23 (10.7%). These were subdivided
into those thought to reflect CNS and peripheral
nervous system (PNS) [95].
2.4.1. Central nervous system dysfunction
2.4.1.1. Dizziness and headache
Headache is a possible symptom in any systemic
viral infection such as SARS-CoV-2. In COVID-19,
headache usually coincides with fever. Headache was
reported in 6.5-14.1% of COVID-19 cases [73, 98, 99].
However, the prevalence of headaches in COVID-19
infection seems to be underestimated in terms of
variety and clinical description. According to this
finding raised by Dr. Robert Belvis [100], headaches
related to COVID-19 can be classified in the 2 phases
of the disease. Acute headache, primary cough
headache, tension type headache, and heterologous
headache caused by systemic viral infection can
appear in Phase I (influenza like phase) and hypoxia
and headache caused by new onset headache can
occur in Phase II (cytokine storm phase with an
increase of IL-2, IL-6, IL-7, IL-10, TNFα, G-CSF, IFN-γ
inducible protein 10, MCP1, and macrophage
inflammatory protein 1-α). Headache may be
associated with cytokine storm in SARS-CoV-2
infection, but further research is needed to better
understand this link.
2.4.1.2. Acute cerebrovascular disease
With the spread of COVID-19 around the world,
there is more and more evidence related to
cerebrovascular diseases and other forms of vascular
diseases. COVID-19 cerebrovascular disease appears
to be predominantly ischemic and involves large
vessels. In the elderly, it reflects the underlying
severity of the systemic disease as well as the
hyperinflammatory state, whereas in the younger
patients, it seems to be due to hypercoagulopathy
[101, 102]. Besides hypercoagulable state,
SARS-CoV-2 can also infect and damage endothelial
cells. However, it remains to be determined whether
the endothelial cell damage caused by the virus or
even the real vasculitis will lead to the
cerebrovascular syndrome associated with COVID-19,
which will require more detailed angiography and
neuropathological analysis.
Stroke may have significant interaction with
COVID-19, and stroke is not uncommon among
patients hospitalized with COVID-19. Several studies
have reported strokes in COVID-19 patients, with
rates ranging from 1%-3% and up to 6% of critically ill
patients [5, 73, 99, 103]. These patients may develop
more severe coagulopathy, defined as
COVID-19-related coagulopathy, which may be
caused by inflammation, including inflammatory
cytokine storms. It is not clear whether these strokes
are caused by SARS-CoV-2 or the incidence rate of
stroke in these high-risk groups, and these high-risk
groups also happened to have SARS-CoV-2.
SARS-CoV-2 infection does play a role in stroke,
which is reasonable, because infection usually
increases the risk of stroke. Therefore, understanding
the relationship between infection and stroke has
taken on urgency in the era of the COVID-19
pandemic. The association of infection and stroke is
also bidirectional. Furthermore, ACE is known for its
role in blood pressure regulation through the renin
angiotensin aldosterone system (RAAS), and it can
also play a role in fertility, immunity, hematopoiesis
and obesity, fibrosis and Alzheimer’s dementia [104].
More importantly, it is a functional receptor of
SARS-CoV-2 [105]. Therefore, understanding the
interaction between SARS-CoV-2 and ACE2 is very
important for the design of therapy for this disease. In
the case of severe infection, myocardial injury and
arrhythmias, such as atrial fibrillation, can lead to
cardiac embolism and cerebral infarction [106]. In
addition to primary viral diseases, a considerable
number of critical patients with COVID-19 may also
have secondary bacteremia. In one case series, about
10% of patients requiring mechanical ventilation have
bacteremia, which increases the risk of stroke by more
than 20 fold [107]. Septic cerebral emboli often lead to
hemorrhage. In a postmortem magnetic resonance
imaging (MRI) study, 10% of brain showed signs of
hemorrhage [108]. Emerging evidence suggested the
role of infection, as a contributor to long-term risk of
atherosclerotic disease and stroke; immune
dysregulation after stroke and its effect on the risk of
stroke-associated infection; and the impact of
infection at the time of stroke on the immune reaction
to brain injury and subsequent cognitive decline [109].
In conclusion, these clinical findings suggest that
SARS-CoV-2 may have adverse effects on brain
through a variety of pathophysiological pathways
and eventually lead to vascular brain injury.
2.4.2. Peripheral nervous system
2.4.2.1. Peripheral organ dysfunctions
COVID-19 also damages other organs, and
metabolic and pathological evidences on
COVID-19-induced renal, cardiac, hepatic,
gastrointestinal and endocrine organ damage have
been presented so far [106, 107, 110, 111]. The
resulting systemic metabolic changes, including water
and electrolyte imbalance, hormonal dysfunction, and

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accumulation of toxic metabolites, may also
contribute to some of the nonspecific neurological
manifestations of the disease, like confusion,
agitation, headache, cardiac involvement, which may
affect brain by reducing cerebral perfusion. The lung
is the most seriously affected organ in COVID-19,
accompanied by a large number of alveolar injuries,
edema, inflammatory cell infiltration, microvascular
thrombosis, microvascular injury and bleeding [112].
SARS-CoV-2 was mainly detected in lung cells and
epithelial progenitor cells [112, 113]. Severe hypoxia
(acute respiratory distress syndrome, ARDS) caused
by respiratory failure caused by lung injury requires
auxiliary ventilation [114]. Consistent with hypoxic
brain damage, the autopsy study of COVID-19
showed that neuronal damage was found in the most
vulnerable areas of brain, including neocortex,
hippocampus and cerebellum [84, 115].
2.4.2.2. Neurological autoimmune disorders with
COVID-19 on PNS
Viral illnesses may trigger an autoimmune
response, which affects the central or peripheral
nervous system. As mentioned earlier, acute
inflammatory demyelinating peripheral neuropathy
(AIDP)/Guillain-Barre syndrome (GBS) may be a
consequence of infection of peripheral nervous
system. MERS also causes post infectious brainstem
encephalitis and GBS [116]. Reports of SARS-CoV-2
transverse myelitis also began to appear [73]. GBS is
an acute polyradiculopathy characterized by rapid
progressive symmetrical limb weakness, sensory
disturbance during examination, and facial weakness
in some patients. 11 patients had GBS with weakness
of all four limbs with or without sensory loss
[117-119], of which three patients only had a paralytic
variant with leg weakness [118, 120, 121], and one had
lower limb paresthesia [118].
2.5. COVID-19 on motor system
Motor complications with COVID-19 such as
critical illness myopathy, polyneuropathy, GBS, Bell’s
palsy, and Parkinson’s disease (PD) have been
reported recently [122].
2.5.1. Autonomic dysfunction preceding acute motor
axonal neuropathy (AMAN)
A 20-year-old patient had previous autonomic
dysfunction characterized by sinus arrhythmia,
postural hypotension, intermittent sweating,
constipation, erectile dysfunction, and chest crush
[123]. This is unique in this case, except for the fact
that autonomic dysfunction precedes motor
weakness, which is very rare. Since the disease
associated with COVID-19 was mild and almost
asymptomatic, the patient was only treated with
acetaminophen. For AMAN, intravenous
immunoglobulin (0.4 g/kg/day, for 5 consecutive
days) was started. After 15 days of treatment, the
patient's dyskinesia and autonomic nervous system
began to improve. After rigorous physical therapy,
the patient was able to walk with some help one
month after admission.
2.5.2. Oculomotor nerve palsy and motor peripheral
neuropathy
A report described a 65 year old man with
oculomotor nerve palsy [124]. He had a 5-day history
of persistent diplopia and left blepharoptosis. MRI
and Magnetic resonance angiography (MRA) showed
no abnormalities, but computed tomography (CT) of
chest showed diffuse ground glass opacity.
SARS-CoV-2 was detected in throat swabs.
Importantly, a case reported that a 69 year old man
was admitted to the COVID-19 ward with bilateral
weakness of lower limbs three days before admission
[120]. Due to chronic cough, he underwent a
COVID-19 swab test in the emergency room and was
admitted to the COVID-19 ward. The strength of his
bilateral knee extension was reduced by four fifths,
the strength of other muscle groups was normal, his
knees and ankles had no convulsions, and his gait was
ataxia. This case is different from the case of GBS
reported in the Journal of Neurology of the Lancet.
There is microbiological evidence of COVID-19
infection at the time of admission, and influenza like
symptoms appear only 7 days after the symptoms
appear. He had distal weakness and hyporeflexia, no
back pain or sensory level, suggesting motor
peripheral neuropathy. However, this diagnosis still
needs further characterization and analysis. At
present, the physical condition of the case does not
allow us to carry out further characterization.
2.5.3. Bell’s palsy
Wan et al. described the first case of Bell’s palsy
in a 65 year old woman who developed left lower
motor neuron facial paralysis 2 days after mastoid
pain. Interestingly, the patient had no symptoms of
other viral diseases [125]. MRI showed no
abnormality, but CT showed a piece of ground glass
shadow in the right lower lung, which was suspected
to be SARS-CoV-2. SARS-CoV-2 infection was
confirmed by real-time reverse transcription
polymerase chain reaction (RT-PCR).
2.5.4. Parkinson’s disease and motor symptom
Patients with underlying neurological
dysfunction, such as PD, often have associated
cardiovascular and respiratory disorders, which
increase their risk of developing severe COVID-19. In
addition, due to fever and altered dopaminergic drug

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intake, PD patients with COVID-19 have developed
Parkinson’s disease high fever syndrome, a motor
disorder emergency [126]. Although patients who
experience this phenomenon may recover from
COVID-19, some patients may leave significant
disabilities, while others may not survive [127].
Recently, people with or without PD participating in
the online study Fox Insight (FI) were invited to
complete a survey to assess COVID-19 symptoms and
the pandemic’s effect. The report showed that people
with PD and COVID-19 experienced new or
worsening motor (63%) symptom. And people with
PD but not diagnosed with COVID-19 reported
disrupted medical care (64%), exercise (21%), and
social activities (57%), and worsened motor (43%)
symptoms [128]. These results suggested that during
COVID-19 infection, people with PD reported
worsening of many PD-related motor and non-motor
symptoms, including rigidity, tremor, walking
difficulties, emotional symptoms, cognition and
fatigue.
2.6. COVID-19 on urinary system
While most COVID-19 patients present with
mild symptoms, a small percentage can gradually
develop acute respiratory distress syndrome and
multiple organ dysfunction syndromes, leading to
death [129]. Because these symptoms may overlap
with other common disease processes, it is difficult to
identify these symptoms as the underlying cause
directly related to COVID-19. Recently, Mumm and
his colleagues reported increased frequency of
urination, and identified this in seven males out of 57
patients currently being treated in COVID-19 wards
[130]. In the absence of any other cause, urinary
frequency may be secondary to viral cystitis due to
the underlying COVID-19 disorder. We recommend
considering urinary frequency as a memory tool for
patients with infectious symptoms to increase
urologists’ awareness during the current COVID-19
pandemic, preventing the fatal effects of erroneous
interpretation of urinary symptoms.
2.6.1. Lower urinary tract symptoms
One of the most frequently reported
epidemiological data is gender related COVID-19
mortality. Studies conducted in various countries
have shown that men are more susceptible to
COVID-19 infection. Male patients accounted for 73%
of deaths in China, 59% of deaths in Korea, and 70% of
patients who died in Italy were male [131, 132]. In
addition, a recent review of current epidemiological
studies of 59254 patients from 11 different countries
suggested an association between male sex and higher
mortality [133]. In addition, experimental studies
performed by Channappanavar and his colleagues
showed that male rats were more susceptible to
SARS-CoV infection than age-matched female rats
[134]. Epidemiological studies of COVID-19 are
essential to better understand the pathogenic
mechanisms of the disease and to identify good
treatment strategies. Lower urinary tract symptoms
(LUTS) are a term that encompasses a wide range of
symptoms that occur after storage and voiding. LUTS
is common in adult men and is often associated with
benign prostatic hyperplasia (BPH) [135]. The
prevalence of BPH increases significantly with age,
and BPH-related LUTS often emerged as a natural
result of aging and androgen exposure. Prostatic
hyperplasia increases urethral resistance, leading to
compensatory changes in bladder function. Because
bladder outlet resistance increases, detrusor pressure
also increases with increasing urine flow. Increased
detrusor resistance also causes LUTS by affecting
bladder storage function [136]. LUTS was assessed by
approved questionnaires, such as the International
Prostate Symptom Score (I-PSS), and the results
indicated that LUTS could effectively predict the
severity of COVID-19.
2.6.2. Acute kidney injury
Acute kidney injury (AKI) has been reported in
up to 25% of critically ill patients with SARS-CoV-2
infection, in particular in those with serious infections,
and has been associated with substantial morbidity
and mortality [137, 138]. In most studies, AKI
develops throughout hospitalization, with a mean of 5
to 9 days after admission [139, 140]. AKI develops
more frequently in patients with the most severe
diseases (especially ARDS, requiring invasive
mechanical ventilation), including elderly patients or
those with hypertension or diabetes. The causes of
kidney involvement in COVID-19 may be
multifactorial, and cardiovascular comorbidity and
predisposing factors (such as sepsis and nephrotoxin)
are important factors. However, renal tubular injury is
common and associated with the cytopathic effect of
renal resident cells and cytokine storm syndrome
[141, 142].
2.7. COVID-19 on reproductive system
Since the emergence of the SARS-CoV-2 infection
in December 2019, it has rapidly spread across all over
the world. Additionally, it has been demonstrated
that SARS-CoV-2 infection not only damage to
respiratory system, but other organs of human, such
as heart, liver, oesophagus, kidney, bladder, and
ileum [143]. As mentioned above, ACE2, the
functional receptor for SARS-CoV-2, modulates the
cleavage of Ang II and Ang 1-7. Because SARS-CoV-2

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enters cells by binding to ACE2 receptor, the
reproductive cells and/or tissues expressing ACE2
may be susceptible to virus infection, and their
functions may be interfered theoretically. ACE2, Ang
II and Ang 1-7 can regulate the basic functions of male
and female reproductive system. In the female, it
includes folliculogenesis, steroidogenesis, oocyte
maturation, ovulation and endometrial regeneration
[144, 145]. In the male, testicular ACE2 may regulate
testicular function, play a role in sperm function, and
may affect sperm contribution to embryo quality [146,
147]. An important and interesting topic in the era of
COVID-19 is the ability of virus to affect male and
female reproductive capacity (Fig. 4), and whether
pregnant women with COVID-19 have an increased
risk of death or comorbidity.
2.7.1. Reproductive hormones
One of the main functions of ovary and testis is
steroid production. Therefore, the evaluation of sex
hormone levels can provide the evaluation of gonadal
function in patients with COVID-19. Ma et al.
compared sex related hormone levels in 119
reproductive men infected with SARS-CoV-2 with 273
age-matched controls [148]. Most patients have
moderate to severe diseases. The serum luteinizing
hormone (LH) was increased and serum Testosterone
(T)/LH ratio was decreased in the COVID-19 group.
Rastrelli et al. found that the deterioration of clinical
condition is accompanied by the gradual decrease of T
level and the increase of LH level [149]. However,
these results should be interpreted with caution, as
pre-infection sex hormone baselines are not available
for these patients. In addition, hypogonadism is a
common systemic disease. In the case of COVID-19, it
is not clear whether the low T level observed is the
result of the direct effect of COVID-19 on gonadal
function [150]. In the female, severe acute illness may
alter hypothalamic pituitary gonadal (HPG) axis
function, reducing endogenous estrogen and
progesterone production [151].
2.7.2. Sex and COVID-19
ACE2 receptor is more abundant in male
reproductive system than in female reproductive
system. ACE2 was low expressed in oviduct (ciliated
cells and endothelial cells), ovary, vagina, cervix and
endometrium [152, 153]. On the other hand, the
expression of ACE2 was the highest in testis, high in
leydig cells and sertoli cells, and medium in seminal
vesicle cells [154, 155]. Therefore, it is expected that
testis is more vulnerable to SARS-CoV-2 infection
than ovary.
2.7.2.1. Male
As we all know, ACE2 not only expresses in the
lung, but also extensively expresses in spermatogonia,
sertoli and leydig cells in testicle. Indeed, it has been
found that the testis may be infected with
SARS-CoV-2, which may lead to further reproductive
system diseases [156, 157]. Similarly, it is well known
that viruses can enter testicular cells, cause viral
orchitis, and even lead to male infertility and
testicular tumors [158, 159]. In ACE2 positive cells, the
abundance of transcripts related to SARS-CoV-2
replication and transmission was higher than that
related to male gametogenesis. The expression of
ACE2 in human testis suggests that SARS-CoV-2 may
infect male gonads and lead to male reproductive
dysfunction. We know that temperature is very
important for cell growth and development, and 37°C
is the best temperature for cell growth. However,
almost all SARS-CoV-2 infected people have
persistent fever. When the human body is in a state of
Figure 4. Effects of COVID-19 on the male and female reproductive systems.

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high fever for a long time, the testicular temperature
will change, and the germ cells will be damaged and
degenerated [160, 161]. Furthermore, several results
showed that SARS-CoV-2 existed in semen and testis
of SARS-CoV-2 infected patients in acute and
convalescent stages. Therefore, it also supports the
result that SARS-CoV-2 can be sexually transmitted
through men [162, 163]. SARS-CoV-2 infection can
cause systemic local inflammation, and due to the
imperfect blood testis/vas deferens/epididymis
barrier, SARS-CoV-2 may propagate to the male
reproductive tract [164]. However, the virus cannot
replicate in the male reproductive system, it may
persist, and this phenomenon may be due to the
special immunity of testis [165, 166]. These results
suggest that sexual transmission may be an important
link in the prevention of transmission. A recent report
on 31 Italian male COVID-19 patients noted that some
patients developed hypergonadotropic hypogona-
dism after disease onset [149]. In this study, low levels
of serum testosterone (total and free) may serve as a
predictor of poor outcome in SARS-CoV-2-infected
men. Testosterone, as a regulator of endothelial
function, inhibits inflammatory responses by
increasing the levels of anti-inflammatory cytokines,
such as IL-10, and decreasing the levels of
pro-inflammatory cytokines, such as TNFα, IL-6, and
IL-1β [167, 168]. Therefore, it can be hypothesized that
suppressed testosterone levels may be one of the
reasons for the large differences in mortality and
hospitalization between men and women and may
also explain why SARS-CoV-2 most commonly infects
elderly men. As mentioned earlier, patients with
hypogonadism have higher concentrations of TNFα,
IL-6 and IL-1β due to reduced inhibition. This
eventually worsens endothelial dysfunction and
further impairs erectile function. While erection is
certainly a trivial matter for patients in ICU, there is
reason to suspect that impaired vascular function may
persist among survivors of COVID-19 and even
become a public health problem in the coming
months. In addition, since erectile function is a
predictor of heart disease [169, 170], investigating
whether erectile dysfunction occurs in patients with
COVID-19 may also be a good alternative indicator of
general cardiovascular function, improving patient
care and quality of life. In addition, only a small
retrospective study assessed the presence of
SARS-CoV-2 in prostate secretions. One study
evaluated prostate secretions from 18 male patients
with confirmed COVID-19 and 5 suspected cases, and
found that no SARS-CoV-2 RNA expression was
detected in the samples of all patients assessed [171].
As any kind of sudden disease, there are more doubts
and hypotheses, rather than certainty, about the
impact of COVID-19 on male reproductive system.
Many studies have been carried out to better
understand the disease and its short- and long-term
effects on health. As has been demonstrated in other
viral diseases, the involvement of male reproductive
system is a possibility, which may reveal a new route
of transmission and/or impact on its function. The
virus has been found in the semen of infected patients,
but its impact on male reproductive health remains to
be further investigated.
2.7.2.2. Female
Studies have shown that ACE2 mRNA is highly
expressed in the ovaries of women of childbearing age
and postmenopausal women. These results implied
that female reproductive system may be at risk of
SARS-CoV-2 infection [172]. Single cell sequencing
was used to analyze the expression of ACE2,
TMPRSS2, cathepsin B and L (CTSB and CTSL,
respectively) in human ovarian cells [173]. It was
found that the expressions of ACE2 in stromal cells
and perivascular cells of ovarian cortex were very
low. TMPRSS2 was not expressed in different types of
oocyte nest cells, while CTSB and CTSL were
expressed in all ovarian cells. There was no
co-expression of ACE2/CTSB and ACE2/CTSL in all
ovarian cell types. Because ACE2 needs the
co-expression of protease TMPRSS2 or CTSB/L to
make protein on its surface and to ensure enter host
cells. The expression rate of ACE2 in ciliated cells,
secretory cells and leukocytes was less than 5%. On
the contrary, the expression levels of protease
TMPRSS2 and CTSL/B were different in different
fallopian tube cells, but CTSL was not detected in any
fallopian tube cells. No co-expression of ACE2,
TMPRSS2 or CTSB was observed in any oviduct cells.
Furthermore, studies have shown that 70
pregnant women infected with SARS-CoV-2 had
symptoms such as fever (84%), cough (28%), and
dyspnea (18%). Obstetric complications included
preterm delivery (39%), intrauterine growth
restriction miscarriage (10%) and miscarriage (2%).
Amniotic fluid, cord blood, throat swabs and neonatal
milk were collected from 9 pregnant women with
SARS-CoV-2 infection in Wuhan, China, and the
results indicated that there was no direct evidence of
vertical transmission of SARS-CoV-2 [174, 175]. But it
was found in additional studies that ACE2 has
transient overexpression and increased activity
during pregnancy, particularly in the placenta,
implying that there may be vertical transmission.
Previous clinical studies have not observed evidence
of vertical transmission of SARS-CoV-2 among cases,
a phenomenon that still needs to be more carefully
investigated in clinical practice [176].

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SARS-CoV-2 may infect ovary, uterus, vagina
and placenta through the universal expression of
ACE2. In addition, SARS-CoV-2/ACE2 may interfere
with female reproductive function, leading to
infertility, menstrual disorders and fetal distress [177].
We recommend following up and evaluating fertility
after recovery from SARS-CoV-2 infection and, if
possible, postponing pregnancy, especially in young
women. Moreover, we should continue to pay
attention to the situation of pregnant patients and
fetus, and take timely measures. In order to reduce the
incidence of SARS-CoV-2 infection, special care was
given to healthy pregnant women, puerpera and
newborns.
COVID-19 sex differences in incidence,
comorbidities, and mortality males are at higher risk
and require prompt action to understand the sources
of biological and behavioral differences. As the impact
of SARS-CoV-2 on male/female reproductive system
becomes more intensively studied, we will control
and prevent the SARS-CoV-2 infection system in the
male/female reproductive system more and more
effectively.
2.8. COVID-19 on digestive system
At the initial stage of COVID-19 pandemic, a
series of respiratory manifestations caused by the
virus are the first to be discovered and concerned.
Thence, SARS-CoV-2 is initially considered to be most
likely to cause respiratory illnesses and spread from
human to human mainly via respiratory tract. Since
SARS-CoV-2 RNA in stool specimen was first
reported in the study of the first case of COVID-19
infection in USA [178]. Ongoing reports of viral
gastrointestinal infection and fecal-oral transmission
of the virus are a matter of widespread concern.
2.8.1. The impact of SARS-CoV-2 on gastrointestinal
tract
The digestive system has been reported not only
as a site of disease expression, but also as a possible
driver of disease severity and viral transmission.
Several studies have reported a high prevalence of
gastrointestinal symptoms in patients infected with
SARS-CoV-2, mainly including loss of appetite,
nausea, vomiting, diarrhea and abdominal pain
[178-180] (Fig. 5). Importantly, multiple studies have
confirmed a fraction of COVID-19 patients only
experience abdominal symptoms without fever or
respiratory manifestations [179, 180]. Therefore, it is
important that clinicians should maintain a high index
of vigilance in patients with gastrointestinal
symptoms. In addition, SARS-CoV-2 appears to
persist in patients’ stool specimen, even though the
patients’ throat swabs become negative [181, 182]. The
study also concluded that patients with
gastrointestinal symptoms have significantly longer
time from onset to hospital admission than patients
without gastrointestinal symptoms [180]. In contrast,
a study reported a low incidence (3.8%) of
gastrointestinal symptoms [67]. Of course, due to the
difference in medical record samples and symptom
ascertainment, different conclusions are normal.
However, the risk of virus transmission here is
unanimously recognized and cannot be ignored.
Figure 5. SARS-CoV-2 infection of the gastrointestinal tract.

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Endoscopic and histologic findings give us a
more comprehensive understanding of the impact of
SARS-CoV-2 on the gastrointestinal tract. In the study,
a patient with COVID-19 present upper gastro-
intestinal bleed [181]. Gastrointestinal endoscopy was
performed and mucosa damage in the esophagus was
observed [181]. Additionally, the hematoxylin-eosin
staining results in this study showed that the mucous
epithelium of esophagus, stomach, duodenum, and
rectum did not appear obvious damage [181].
What’s more, the incidence of liver injury in
COVID-19 patients is 39.6% to 43.4%, which is mainly
manifested by increased levels of alanine amino-
transferase (ALT) and aspartate aminotransferase
(AST), as well as hypoalbuminemia [183, 184]. In
contrast, some other studies did not find significant
liver injury in COVID-19 patients [180, 185]. However,
the study also reported that patients with digestive
symptoms had higher mean liver enzyme levels and
longer prothrombin time than those without digestive
symptoms, which could reflect the potential risk of
liver injury [185]. It is hard to explain the variations in
liver test abnormalities among those studies, thus the
effect of SARS-CoV-2 on liver needs further research.
More importantly, another study showed that
patients with gastrointestinal symptoms were
reported more likely to suffer liver injury due to their
elevated ALT and AST compared with patients
without gastrointestinal symptoms [180].
2.8.2. Why gastrointestinal tract occurs?
There are many proposed reasons for the
occurrence of viral gastrointestinal infection. First,
gastrointestinal epithelial cells has been shown to
express ACE2, the receptor of SARS-CoV-2 [181].
Moreover, the positive staining of ACE2 and
SARS-CoV-2 was also observed in gastrointestinal
epithelium from other patients who tested positive for
SARS-CoV-2 RNA in feces [181]. Second, SARS-CoV-2
damages the digestive system through an
inflammatory response. The intestine is the largest
immune organ in the human body, and COVID-19
patients present high inflammatory level [186]. The
chain reaction of inflammatory factors and viremia
may injure the digestive system. Finally, the intestinal
flora plays an important role in body. The number of
intestinal flora in the human intestine is astonishing
and diverse, which is very important for the normal
functioning of digestive system. The virus in the
intestine may cause disorders of intestinal flora,
which result in digestive symptoms [187]. Several
studies have also reported dysbiosis of intestinal flora
in COVID-19 patients [188, 189]. In a study, the author
observed that gut virome and bacteriome in the
COVID-19 patients are notably different from those of
the healthy control, and this difference also exists
between patients of different severity [188]. The study
also confirmed the virome differences and bacteriome
dysbiosis in mouse COVID-19 model. More
importantly, the study reported the differential
expression of immune/infection-related genes in
mouse intestinal epithelial tissues during infection,
such as the polymeric immunoglobulin receptor
(PIGR), interleukin-15 (IL-15), and tribbles
pseudokinase 1 (TRIB1) [188]. Therefore, SARS-CoV-2
may cause the changes in the expression of certain
genes in gastrointestinal tissues, which may be related
to the occurrence of gastrointestinal symptoms. In
conclusion, the correlation between gastrointestinal
symptoms and patients’ symptoms, diagnosis,
treatment, and outcomes have not been fully
elucidated. It is important and worthy for us to keep
exploring.
3. Treatment of COVID-19
The outbreak of the COVID-19 pandemic has
plunged the world into an unprecedented crisis. The
virus quickly swept across the globe, causing
enormous loss of life, destroying the livelihoods of
billions of people and endangering the global
economy [190]. The cumulative number of confirmed
cases of COVID-19 worldwide has not yet peaked and
the situation remains serious, so the United Nations is
leading and coordinating global efforts to support
countries in their efforts to combat the pandemic.
However, up to now, there is still no good effective
treatment for COVID-19 [191]. Therefore, it has forced
many countries and regions around the world to
quickly carry out the research of the novel
coronavirus.
Particularly, the development of preventive
vaccine against SARS-CoV-2 is the key to control and
prevent the outbreak of a pandemic [192]. According
to the research progress of the COVID-19 vaccine
updated by the World Health Organization, so far
there are 81 new coronavirus vaccines in the clinical
development stage, and more than 180 vaccines are in
the preclinical development stage [193]. Simultaneous
research and development of multiple vaccines will
ensure the quality of the vaccine. The acceleration of
scientific research and clinical trials and the granting
of emergency use authorization by the relevant
government will enable the vaccine to be put on the
market as soon as possible to deal with the sudden
spread of the COVID-19. In addition to vaccines, an
important strategy for the control and treatment of
COVID-19 is to modulate the immune system using
other methods, including the plasma therapy,
suppressing inflammatory cytokines, kinases
inhibitors, cell-based therapies, complement therapy,

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monoclonal antibody therapy and immune
potentiator (Table 1), which are the key
immunotherapeutic approaches to deal with
COVID-19.
3.1. Plasma therapy
It has been demonstrated that convalescent
plasma from COVID-19 patients that have recovered
from the SARS-CoV-2 infection can be utilized as
therapy for patients with COVID-19, without severe
adverse events [194]. Plasma therapy works by
passive transfer antibodies to neutralize the virus.
Clinical data suggested that patients treated with
convalescent plasma had lower mortality than those
who were not [195]. However, this method requires
the collection of plasma from a sufficient number of
convalescent patients. Because of this limitation,
plasma therapy is considered as an option for the
treatment of patients with severe COVID-19.
Importantly, during the progression of the COVID-19
disease, the quality of neutralizing antibodies in
convalescent plasma samples has changed, and
different plasma samples exhibited different antiviral
potentials. Therefore, it is necessary to estimate the
function and titer of neutralizing antibodies from the
donors before treatment [196].
3.2. Cytokine inhibition
The patients with severe COVID-19 were more
likely to generate the cytokine storm, leading to tissue
damage and multi-organ failure. A huge release of
IL-1β, IL-2, IL-6, IL-10, GM-CSF, TNFα, and MCP-1
resulted in immune dysregulation. Therefore, the use
of immunomodulators is beneficial to regulate the
imbalanced immune responses. Current studies
revealed the role of IL-6 in the pathogenesis of
COVID-19, and the development of drugs targeting
the IL-6 pathway is promising for relieving
inflammation in COVID-19 patients [40]. Tocilizumab,
a monoclonal antibody targeting the IL-6 pathway,
has been approved to treat COVID-19. After treatment
with Tocilizumab, the clinical manifestations of
patients have been improved, including rapid control
of fever and improved respiratory function [197].
Similarly, monoclonal antibodies available for
COVID-19 therapy are Anakinra, Etanercept,
Mavrilimumab, and Bevacizumab, which target the
IL-1R, TNFα, GM-CSF, VEGF, respectively, and have
been summarized in Table 1.
3.3. Kinase inhibitors
Janus associated protein kinase (JAK) is a
potential therapeutic target for controlling
SARS-CoV-2 infection. Baricitinib, upadacitinib,
fedratinib, and ruxolitinib, as JAK inhibitors, have
been approved for treating rheumatoid arthritis and
multiple inflammatory diseases. Currently, a
randomized, double-blind, placebo-controlled,
parallel-group Phase III clinical trial of baricitinib in
COVID-19 patients is ongoing, the aim of which is to
investigate whether the baricitinib is effective in
COVID-19 hospitalized patients (NCT04421027).
Bruton tyrosine kinase (BTK) inhibitors are another
group of tyrosine kinase inhibitors. AstraZeneca
initiated a randomized, global clinical trial to evaluate
the efficacy of the acalabrutinib, one of BTK inhibitors,
in the treatment of patients with COVID-19
accompanied by cytokine storm (NCT04497948).
Other kinase inhibitors available for COVID-19
treatment, including sunitinib, a receptor tyrosine
kinase (RTK) inhibitor, and erlotinib, an epidermal
growth factor receptor (EGFR) tyrosine kinase
inhibitor, were shown to block SARS-CoV-2 entry
[198].
3.4. Cell-based therapies
Accumulating evidence has revealed that the
number of NK cells in peripheral blood was
significantly decreased and most of them displayed a
functional exhaustion phenotype in COVID-19
patients. With this in mind, the lack and exhaustion of
NK cells may be one of the reasons for the
unrestricted progression of COVID-19. CYNK-001 is
the allogenic, human placental hematopoietic stem
cell-derived NK cells that can recognize and kill the
virus-infected host cells. A Phase I/II clinical trial is
evaluating its safety, tolerability, and efficacy in
COVID-19 patients (NCT04365101). Another Phase
I/II clinical trial in patients with COVID-19 is
ongoing, which aims to investigate the efficacy of the
constructed NKG2D-ACE2 CAR-NK cells derived
from cord blood in treating severe and critical
COVID-19 (NCT04324996).
Mesenchymal stem cells (MSCs) are a population
of multipotent stem cells with high potential ability of
self-renewal, proliferation, multi-directional differen-
tiation and immunomodulatory [199]. MSCs have an
immunosuppressive effect on different immune cells,
such as T cells, B cells, NK cells and DCs, through
producing a large number of immunosuppressive
agents, including indoleamine-pyrrole 2,
3-dioxygenase (IDO), prostaglandin E2 (PGE2) and
IL-10. Several studies have reported that MSCs served
as a treatment against COVID-19-related cytokine
storm and lung injury. The clinical trials of seven
patients with severe COVID-19 has confirmed the
efficacy and safety of intravenous administration of
MSCs resulting from increasing lymphocyte and
anti-inflammatory cytokines (IL-10) and decreasing
pro-inflammatory cytokines, such as C-reactive
protein (CRP) and TNF [200].

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Table 1. Therapeutic strategies for COVID-19.
Treatment strategy
Agents
Therapeutic target
Function mechanism
Plasma Therapy
Convalescent plasma from
COVID-19 patients
Viral proteins
Transferring antibodies to neutralize the virus
Cytokine therapy
Tocilizumab, Sarilumab, Siltuximab,
Sirukumab, Clazakizumab
IL-6, soluble and membrane
bound IL-6R
Downregulating the JAK-STAT signaling pathway, inhibition of cytokine storm
Anakinra
IL-1R
Inhibition of inflammatory responses and cytokine storm, alleviated lung injury
Etanercept
TNFα
Mavrilimumab, TJ003234,
Gimsilumab, Lenzilumab
GM-CSFR, GM-CSF
Reduced inflammatory responses and alleviated lung injury
Bevacizumab
VEGF
Relieving lung injury
IFNs prescription
IFN-β-1b, IFN-λ
Enhanced antiviral defense
Kinase inhibitor
Fedratinib, Ruxolitinib, Baricitinib
JAK
Blocking SARS-CoV-2 trafficking, alleviating inflammatory responses and
cytokine storm, improved the lung injury
Ibrutinib, Acalabrutinib,
Zanubrutinib
BTK
Blocking B cell proliferation and cytokine release
Sunitinib
RTK
Blocking membrane trafficking of SARS-CoV-2
Erlotinib
EGFR
Blocking membrane trafficking of SARS-CoV-2
Cell-based therapy
NK cells transplantation
NK cells
Restoration of NK cells numbers and activity, enhanced antiviral defense
MSC transplantation
MSC
Increased lymphocyte and anti-inflammatory cytokines and decreased
pro-inflammatory cytokines, improved the lung injury
Tregs adoption
Treg
Anti-inflammation
Monoclonal antibody
therapy
Bamlanivimab
SARS-CoV-2 Spike protein
Neutralizing the virus and preventing the virus from entering the cell to
proliferate
Etesevimab
REGEN-COV
Sotrovimab
4A8
Complement
inhibition
Eculizumab
C5
Reduced inflammatory responses, reduced neutrophil counts, and improved
lung function and lymphocyte recovery
AMY-101
C3
Blood purification
Cytosorb
Cytokines, DAMPs, PAMPs
Prevention of cytokine storm
The balance between effective T cells (Teffs) and
Tregs in the adaptive immune response is most likely
a major factor influencing the outcome of COVID-19
[51, 201]. A clinical study aimed to analyze the global
T cell receptor (TCR) repertoire of peripheral blood
derived Tregs and Teffs, to better understand the
nature of Tregs and Teffs against COVID-19, and to
reveal biomarkers associated with disease severity
(NCT04379466). This is great meaningful for
understanding the pathophysiology of the disease
and designing therapeutics and vaccines.
3.5. Monoclonal antibody therapy
Monoclonal antibodies, which accurately
identify and destroy antigens, play an important role
in disease diagnosis, anti-infection, and anti-tumor.
For viral infections, a neutralizing monoclonal
antibody can specifically neutralize the virus and
prevent the virus from entering the cell to proliferate.
Thus, neutralizing monoclonal antibodies are
regarded as one of the most promising options for the
prevention and treatment of COVID-19. At present,
the SARS-CoV-2 S protein-targeting monoclonal
antibodies are mainly the receptor binding domain
(RBD)-targeting antibodies [202-205]. Bamlanivimab
(LY-CoV555) is a neutralizing monoclonal antibody
that binds to the RBD of SARS-CoV-2 S protein, and
has been shown in Phase II trial to significantly reduce
SARS-CoV-2 levels in patients [202]. According to the
U.S. Food and Drug Administration (FDA)
announcement, Bamlanivimab was the first
monoclonal antibody which receive the emergency
use authorization (EUA) on November 9, 2020.
Etesevimab (LY-CoV016) is another neutralizing
monoclonal antibody that also binds to the RBD of
SARS-CoV-2 S protein [203].The combination therapy
of Bamlanivimab and Etesevimab accelerated the
decline of SARS-CoV-2 viral load and reduced the
mortality rate of COVID-19 patients [203, 206], and
obtained the EUA granted by FDA on February 9,
2021. Unfortunately, whether it was the use of
Bamlanivimab alone or the combined treatment of
Bamlanivimab and Etesevimab, these have been
shown to be unable to resist the mutant virus.
REGEN-COV, combination monoclonal antibodies of
Casirivimab (REGN10933) and Imdevimab
(REGN10987) which bind to the RBD of SARS-CoV-2
S protein [204, 205], has also obtained the EUA from
FDA on November 21, 2020, and more importantly,
REGEN-COV still retains its effectiveness against a
variety of mutant viruses [205]. Sotrovimab
(VIR-7831), a monoclonal antibody which also binds
to the RBD of SARS-CoV-2 S protein has shown that
the risk of hospitalization or death in the Sotrovimab
group was 85% lower than that of the control group
[207], and Sotrovimab obtained the EUA from FDA on
May 26, 2021. Additionally, 4A8, as an N-terminal
domain (NTD)-targeting antibody, has a strong virus
neutralization ability [208]. Combination of the
NTD-targeting antibody with RBD-targeting antibody
may avoid the escaping mutations of the virus and

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serve as promising “cocktail” therapeutics. Of course,
there are many other monoclonal antibodies for the
treatment of COVID-19 in the research and
development stage or clinical trial stage, and it is of
great significance and contribution to the fight against
the global epidemic.
3.6. Other therapies
An adjunctive therapy available for COVID-19 is
cytosorb, which absorbs a broad spectrum of
cytokines, damage-associated molecular patterns
(DAMPs), and pathogen-associated molecular
patterns (PAMPs) in the blood circulation to reduce
inflammation and improve immunopathology of the
disease [209]. Complement inhibitors have emerged
as the drug candidates against SARS-CoV-2 infection.
In a cohort study, COVID-19 patients were treated
with the eulizumab and the cyclic peptide AMY-101
to block complement C5 and C3, respectively, and it
was shown that complement inhibition alleviated
hyper-inflammation characterized by a significant
decrease in serum IL-6 and CRP, reduced neutrophil
counts, and markedly improved lung function and
lymphocyte recovery [210]. Because the surface
ligands of SARS-CoV-2 are constantly altered to
escape neutralizing antibodies, one strategy is to
apply drugs that block receptors for such ligands on
host cells, such as ACE2. Immune potentiator
treatment strategies aim to stimulate innate and
adaptive immunity through multiple mechanisms to
eliminate viral infections. These potentiators include
antimicrobial peptides, immune checkpoint
inhibitors, pattern recognition receptor (PRR) ligands,
and signaling compartments [211]. Neutralizing
antibodies against PD-1, alone or in combination with
thymosin, are under investigation for their efficacy in
COVID-19 cases (NCT04268537). Additionally, the
use of corticosteroid to treat patients with COVID-19
remains controversial currently, and relevant clinical
trials are ongoing (NCT04244591).
4. Conclusions and Perspectives
Similar to SARS, COVID-19 manifests mainly as
the symptoms of respiratory system, but emerging
evidences as mentioned above suggest that
SARS-CoV-2 affects various other systems in humans
as well. Clinical manifestations of multisystem
infection are more unpredictable to thus make the
treatment of COVID-19 more difficult. Therefore, it is
necessary to perform a comprehensive physical
assessment and provide a systematic therapeutic
schedule for each inpatient, maybe with different
symptoms. The review provides a novel perspective
on COVID-19 from the infection with multisystem
involvement to help the health and medical
community to acquire available information.
Additionally, scientific researches still need to be
funded and executed to reveal more details about the
molecular mechanism of SARS-CoV-2 to solve the
following three solemn problems: (1) How to
diagnose accurately as early as possible? (2) How to
effectively control the spread of the virus? (3) How to
cure the COVID-19 efficiently?
Acknowledgments
Funding
The work was supported by the National
Natural Science Foundation of China (62005085), and
the China Postdoctoral Science Foundation
(2021M691093).
Author Contributions
QS, JL, HCC, ZZ, SG and QHW conceived and
drafted the manuscript. HCC, QS, ZZ and SG drew
the figures. HCC discussed the concepts of the
manuscript. XRA checked the manuscript.
Competing Interests
The authors have declared that no competing
interest exists.
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Author Biography
Qi Shen has completed her Ph.D. degree from
South China Normal University and currently
working here as a postdoctoral scientist. She has
published more than 10 articles on neurobiology in
well reputed journals including Aging Cell and Stem
Cell Research and Therapy as first or coauthor. Her

Int. J. Biol. Sci. 2022, Vol. 18
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research line focuses on the related mechanisms of
neurodegenerative diseases, depression, SARS-CoV-2,
atherosclerosis and other diseases, and the
exploration of potential treatment methods.
Zhan Zhang is a doctoral student majoring in
basic medicine at Sun Yat-sen Memorial Hospital, Sun
Yat-sen University. His current research focuses on
the pathogenesis of neurodegenerative diseases and
brain injury diseases, especially radiation-induced
brain injury. The research was mainly published in
Aging Cell, Stem Cell Research & Therapy and The
FASEB Journal.
Haocai Chang earned his Ph.D. degree in
Biophysics from South China Normal University in
2019. As the first author or corresponding author, he
published articles in Advanced Science, Journal of
Hematology & Oncology, Cancer Letters, and other
journals. His main research field is the development
of T and B cells and the regulation of their
intracellular signal transduction under specific
pathological models, including tumors and infections.
In particular, he focuses on developing some new
approaches to regulate immune response, including T
and B cell immunity, and then to alleviate or treat
those diseases.